Copper-catalyzed synthesis of 5-substituted 1H-tetrazoles via the [3+2] cycloaddition of nitriles and trimethylsilyl azide

Article abstract of DOI:10.1016/j.tetlet.2008.02.115

The [3+2] cycloaddition between various nitriles and trimethylsilyl azide proceeds smoothly in the presence of a Cu^I catalyst in DMF/MeOH, to give the corresponding 5-substituted 1H-tetrazoles in good to high yields. The reaction most probably proceeds through the in situ formation of a copper azide species, followed by a successive [3+2] cycloaddition with the nitriles.

Full text of DOI:10.1016/j.tetlet.2008.02.115

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Tetrahedron Letters 49 (2008) 2824–2827
Copper-catalyzed synthesis of 5-substituted 1H-tetrazoles via the
[3+2] cycloaddition of nitriles and trimethylsilyl azide
Tienan Jin, Fukuzou Kitahara, Shin Kamijo, Yoshinori Yamamoto *
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 17 January 2008; revised 4 February 2008; accepted 21 February 2008
Available online 4 March 2008
Abstract
The [3+2] cycloaddition between various nitriles and trimethylsilyl azide proceeds smoothly in the presence of a CuI catalyst in DMF/
MeOH, to give the corresponding 5-substituted 1H-tetrazoles in good to high yields. The reaction most probably proceeds through the
in situ formation of a copper azide species, followed by a successive [3+2] cycloaddition with the nitriles.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 5-Substituted 1H-tetrazole; [3+2] Cycloaddition; Nitrile; Copper catalyst; Copper azide; Trimethylsilyl azide
Tetrazoles are regarded as biologically equivalent to the
carboxylic acid group, and extensive work on the synthesis
of tetrazoles has been carried out in the field of material sci-
ences, pharmaceuticals, explosives, and photography.1 The
synthesis of 5-substituted 1H-tetrazoles from nitriles has
received much attention recently, and new preparative
methods have appeared.2 Recently, Sharpless and co-work-
ers reported an innovative and safe procedure for the
preparation of 5-substituted 1H-tetrazoles from the corre-
sponding nitriles and NaN3 in the presence of a stoichio-
metric amount or 50 mol % of Zn(II) salts.3 Later, Pizzo
and co-workers reported an efficient method for the synthe-
sis of tetrazoles by the reaction of nitriles with TMSN3
using 50 mol % of TBAF as catalyst.4 More recently,
Lakshmi Kantam and co-workers efficiently synthesized
tetrazoles by reaction of nitriles with NaN3 using nanocrys-
talline ZnO or zinc hydroxyapatite as the catalyst at 120–
130 °C.5 The development of a catalytic synthetic method
for tetrazoles still remains an active research area. In con-
tinuation of our interest in the development of efficient and
environmentally friendly methods for the catalytic synthe-
sis of nitrogen-containing heterocycles, such as tetrazoles
and 1,2,3-triazoles, through 1,3-dipolar cycloaddition,6
we report herein the synthesis of 5-substituted 1H-tetra-
zoles 2 by the copper-catalyzed [3+2] cycloaddition
between the corresponding nitriles 1 and trimethylsilyl
azide in MeOH/DMF (Eq. 1).
In the cycloaddition reaction between p-methoxybenzo-
nitrile 1a and TMSN3, we investigated the effect of solvents
and metal catalysts on the formation of tetrazole 2a (Table
1). Among the solvents tested (using 2.5 mol % of Cu2O),
DMF gave a low yield of 2a whereas the yield was dramat-
ically improved using a 9:1 mixture of DMF and MeOH
i
(entries 1 and 2).6b,c Other protic solvents such as PrOH
and H2O were also effective (entries 3 and 4). We next
investigated the effect of the metal catalysts. Among the
copper catalysts tested, Cu2O gave the best result at
80 °C (entry 2); CuBr exhibited high catalytic activity,
although a higher reaction temperature was needed (entry
5). Other copper catalysts such as CuCl, CuI, CuCl2, CuBr2
and CuO gave lower yields of 2a (entries 6–10). The reac-
tion without a copper catalyst gave a low yield (entry
11). Other metal catalysts such as AuCl and ZnBr2 were
less effective (entries 12 and 13).
H
2.5 mol% Cu O
2
R
N
+
TMSN
3
R
CN
N
ð1Þ
DMF/MeOH, 80 oC
*
N
Corresponding author. Tel.: +81 22 795 6581; fax: +81 22 795 6784.
N
2
1
E-mail address: yoshi@mail.tains.tohoku.ac.jp (Y. Yamamoto).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.115

T. Jin et al. / Tetrahedron Letters 49 (2008) 2824–2827
2825
Table 1
The results of the [3+2] cycloaddition reaction of various
nitriles 1 with TMSN3 are summarized in Table 2.7 The
reactions of the arylnitriles 1a and 1b, bearing an elec-
tron-donating group at the para-position of the aromatic
ring, with trimethylsilyl azide were carried out in a mixture
of MeOH and DMF (1:9) at 80 °C in the presence of
2.5 mol % Cu2O. The reactions were complete in 12 h
affording the corresponding tetrazoles 2a and 2b in 84%
and 79% yields, respectively (entries 1 and 2). The nitriles
1c and 1d, having an electron-withdrawing NO2 group at
the para- or meta-position, produced the corresponding tet-
razoles 2c and 2d in excellent yields (entries 3 and 4). Nitrile
1e containing an unprotected hydroxy group at the para-
position also gave the product tetrazole 2e in a high yield
(entry 5). Other aryl nitriles such as 2-cyanonaphthalene
1f also reacted without any problems to give the corre-
sponding tetrazole 2f in a high 92% yield (entry 6). The
reaction of sterically hindered ortho-substituted aryl nitrile
1g afforded the desired tetrazole 2g in 50% yield, although
Effect of catalyst and solvent on the formation of tetrazole 2a from 1aa
Entry
Catalyst
Solvent (ratio)
Yield of 2ab (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
a
Cu2O (2.5 mol %)
Cu2O (2.5 mol %)
Cu2O (2.5 mol %)
Cu2O (2.5 mol %)
CuBr
CuCl
CuI
CuCl2
CuBr2
CuO
None
AuCl
ZnBr2
DMF
46
MeOH/DMF (1/9)
iPrOH/DMF (1/9)
H2O/DMF (1/9)
MeOH/DMF (1/9)
MeOH/DMF (1/9)
MeOH/DMF (1/9)
MeOH/DMF (1/9)
MeOH/DMF (1/9)
MeOH/DMF (1/9)
MeOH/DMF (1/9)
MeOH/DMF (1/9)
MeOH/DMF (1/9)
95 (84)c
77
86
(85)
(67)
69
64
72
78
34
(16)
32
The reaction of 1a with TMSN3 (1.5 equiv) was carried out in the
presence of 5 mol % of catalyst at 100 °C for 24 h.
b
1H NMR yield was determined by using dibromomethane as an
internal standard. Isolated yield is shown in parentheses.
c
2.5 mol % of Cu2O was used at 80 °C for 12 h.
Table 2
Cu-catalyzed synthesis of 5-substituted 1H-tetrazoles 2a
Entry
Substrate
1
Time (h)
12
Product
2
Yieldb (%)
84
Mp (°C)
MeO
1
1a
2a
231–233
MeO
CN
H
N
N
N
N
Me
H
2
3
1b
1c
12
12
2b
2c
79
96
248–249
219–220
Me
CN
N
N
N
N
O2N
H
O2N
O2N
CN
N
N
N
N
N
N
NO2
4
CN
1d
12
2d
91
178–179
H
N
O2N
HO
O2N
HO
N
H
5
6
1e
1f
12
12
2e
2f
87
92
234–235
205–206
CN
N
N
N
N
CN
H
N
N
N
N
H
N
CN
N
7
1g
24
2g
50c
149–151
N
N

2826
T. Jin et al. / Tetrahedron Letters 49 (2008) 2824–2827
Table 2 (continued)
Entry
Substrate
1
Time (h)
12
Product
2
Yieldb (%)
77
Mp (°C)
H
Ts
N
8
1h
2h
133–135
Ts CN
N
N
N
H
N
CN
CN
9
1i
24
24
24
2i
66
55
36
123–124
40–42
—
N
N
N
N
N
H
N
10
1j
2j
N
H
N
11
1k
2k
CN
N
N
N
a
Unless otherwise noted, the reaction of nitriles 1 with TMSN3 (1.5 equiv) was conducted in MeOH/DMF (1:9, 0.5 M) in the presence of 2.5 mol % of
Cu2O at 80 °C for the time shown in Table 2.
b
Isolated yield.
c
The reaction was carried out in the presence of 10 mol % of Cu2O at 120 °C.
a prolonged reaction time, higher temperature and larger
amount of catalyst were required (entry 7). The above re-
sults indicate that the tetrazole-forming reaction tolerates
a wide range of functional groups and the [3+2] cycloaddi-
tion proceeds well irrespective of the position and elec-
tronic nature of the substituents on the aromatic ring.
The tosyl nitrile 1h, which has a heteroatom directly linked
to CN, reacted smoothly with TMSN3, giving the corre-
sponding tetrazole 2h in 77% yield (entry 8). Next we inves-
tigated the reactivity of the alkyl nitriles 1i–k. The reaction
of benzylnitrile 1i, valeronitrile 1j and sterically bulky
pivalonitrile 1k furnished the desired tetrazoles 2i–k in
good to moderate yields, although longer reaction times
were needed (entries 9–11).
of nitrile 1 and CuN3 takes place readily to form the inter-
mediate B; precoordination of the nitrogen atom of the CN
group of 1 with copper azide to form complex A would
accelerate this cyclization step. Protonolysis of the interme-
diate B by HN3 affords the 5-substituted 1H-tetrazole 2 and
copper azide catalyst.
a
20 mol% CuN
3
2a
92%
(2)
b
MeOH/DMF (1/9)
80 o C, 12 h
+
CN
NaN
MeO
3
(3)
1a
2a
0%
c
MeOH/DMF (1/9)
80 oC, 12 h
A plausible mechanism is shown in Scheme 1. Initially,
Cu2O reacts with HN3 to produce the CuN3 catalytic spe-
cies; HN3 is formed in situ via the reaction of TMSN3 with
MeOH.8 The [3+2] cycloaddition between the C–N bond
a CuN3 was prepared insitu by mixing NaN3 with
CuI in DMF at rt for 30 min:
b 1H NMR yield was determined using dibromomethane
as an internal standard:
c 1a was recovered in 89% NMR yield:
Cu O
2
HN
TMSN
+
MeOH
3
3
H
N
R
To obtain support for the proposed mechanism, the follow-
ing experiments were carried out. The reaction of 1a
(1 equiv) with NaN3 (1.5 equiv) in the presence of
20 mol % of CuN3, which was generated in situ from
NaN3 (0.2 equiv) and CuI (0.2 equiv),9 in MeOH/DMF
(1/9) gave the corresponding tetrazole 2a in 92% NMR
yield (Eq. 2). On the other hand, the reaction of 1a with
NaN3 in MeOH/DMF (1/9) did not proceed at all in the
absence of the in situ generated CuN3 catalyst, and the
starting material 1a was recovered in 89% NMR yield
(Eq. 3). These results clearly indicate that, (1) CuN3 is a
key catalytic species which enables the [3+2] cycloaddition
with 1a to produce B, (2) the reaction of B with NaN3 pro-
duces CuN3 together with the sodium tetrazole salt which
H O
2
TMSOMe
N
N
CuN
3
N
2
R
C N
1
HN
3
Cu
N
R
C N
R
Cu
N
N
N N
N
N
B
A
Scheme 1. A plausible mechanism for the formation of tetrazoles 2.

T. Jin et al. / Tetrahedron Letters 49 (2008) 2824–2827
2827
V.; Shiva Kumar, K. B. Synth. Commun. 2006, 36, 1809; (c)
LakshmiKantam, M.; Shiva Kumar, K. B.; Phani Raja, K. J. Mol.
Catal. A: Chem. 2006, 247, 186.
undergoes protonolysis with MeOH to give 2a, and (3) the
[3+2] cycloaddition of 1a with NaN3 does not take place.
We are now in a position to synthesize 5-substituted tet-
razoles 2 with a wide range of substituents in good to high
yields through the efficient and convenient copper-cata-
lyzed cycloaddition reaction between nitriles 1 and trimeth-
ylsilyl azide. The reaction most likely proceeds through the
in situ formation of a copper azide catalytic species, fol-
lowed by a successive [3+2] cycloaddition with the nitrile.
6. (a) Kamijo, S.; Huo, Z.; Jin, T.; Kanazawa, C.; Yamamoto, Y. J. Org.
Chem. 2005, 70, 6389; (b) Jin, T.; Kamijo, S.; Yamamoto, Y.
Tetrahedron Lett. 2004, 45, 9435; (c) Jin, T.; Kamijo, S.; Yamamoto,
Y. Eur. J. Org. Chem. 2004, 3789; (d) Kamijo, S.; Jin, T.; Huo, Z.;
Yamamoto, Y. J. Org. Chem. 2004, 69, 2386; (e) Kamijo, S.; Jin, T.;
Yamamoto, Y. Tetrahedron Lett. 2004, 45, 689; (f) Kamijo, S.; Jin, T.;
Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 7786; (g)
Kamijo, S.; Jin, T.; Huo, Z.; Gyong, Y.-S.; Yamamoto, Y. Mol.
Diversity 2003, 6, 181; (h) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y.
Tetrahedron Lett. 2002, 43, 9707; (i) Kamijo, S.; Jin, T.; Yamamoto, Y.
J. Org. Chem. 2002, 67, 7413.
Acknowledgement
7. The procedure for the synthesis of the tetrazole 2a is representative.
Trimethylsilyl azide (0.1 ml, 0.75 mmol) was added to a DMF and
MeOH solution (1 ml, 9:1, 0.5 M) of Cu2O (1.8 mg, 0.0125 mmol) and
p-methoxybenzonitrile 1a (66.6 mg, 0.5 mmol) in a pressure vial. The
reaction mixture was stirred at room temperature for 10 min then
heated at 80 °C for 12 h. After consumption of 1a, the reaction
mixture was cooled to room temperature and extracted with ethyl
acetate. The organic layer was washed with 1 N HCl, dried with
anhydrous Na2SO4, and concentrated. To the residue was added
0.25 N NaOH and the resulting mixture was stirred for 30 min at
room temperature. The mixture was washed with ethyl acetate, and
then concd HCl was added until the pH value of the water layer
became 1. The aqueous layer was extracted with ethyl acetate (ꢀ3)
and the combined organic layers were washed with 1 N HCl. The
organic layer was dried over anhydrous Na2SO4 and concentrated.
The tetrazole 2a was obtained in 84% yield as a white solid (73.7 mg),
mp = 231–233 °C. 1H NMR (400 MHz, DMSO-d6): d 3.83 (3H, s),
7.14 (2H, d, J = 9.0 Hz), 7.96 (2H, d, J = 9.0 Hz); 13C NMR
(100 MHz, DMSO-d6): 55.41, 114.74, 116.20, 128.50, 154.64, 161.30;
IR (KBr) 3200–3300 (br), 1298, 1184, 1035, 750 cmꢁ1; Anal. Calcd for
C8H8N4O: C, 54.53; H, 4.58; N, 31.81. Found: C, 54.60; H, 4.83; N,
32.06. HRMS (EI) calcd for C8H7N4O ([MꢁH]ꢁ) 175.0625. Found
We thank the faculty members in the Instrumental Anal-
ysis Center at Tohoku University for the measurements of
NMR spectra, mass spectra, and elemental analysis.
References and notes
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175.0622. All the 5-substituted tetrazole products
2 are known
compounds and the spectral data and melting points are identical to
those reported in the literatures.
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